title: Coadministration of polyinosinic:polycytidylic acid and immunostimulatory complexes modifies antigen processing in dendritic cell subsets and enhances HIV gag-specific T cell immunity.
abstract: Currently approved adjuvants induce protective Ab responses but are more limited for generating cellular immunity. In this study, we assessed the effect of combining two adjuvants with distinct mechanisms of action on their ability to prime T cells: the TLR3 ligand, polyinosinic:polycytidylic acid (poly I:C), and immunostimulatory complexes (ISCOMs). Each adjuvant was administered alone or together with HIV Gag protein (Gag), and the magnitude, quality, and phenotype of Gag-specific T cell responses were assessed. For CD8 T cells, all adjuvants induced a comparable response magnitude, but combining poly I:C with ISCOMs induced a high frequency of CD127(+), IL-2-producing cells with decreased expression of Tbet compared with either adjuvant alone. For CD4 T cells, combining poly I:C and ISCOMs increased the frequency of multifunctional cells, producing IFN-γ, IL-2, and TNF, and the total magnitude of the response compared with either adjuvant alone. CD8 or CD4 T cell responses induced by both adjuvants mediated protection against Gag-expressing Listeria monocytogenes or vaccinia viral infections. Poly I:C and ISCOMs can alter Ag uptake and/or processing, and we therefore used fluorescently labeled HIV Gag and DQ-OVA to assess these mechanisms, respectively, in multiple dendritic cell subsets. Poly I:C promoted uptake and retention of Ag, whereas ISCOMs enhanced Ag degradation. Combining poly I:C and ISCOMs caused substantial death of dendritic cells but persistence of degraded Ag. These data illustrate how combining adjuvants, such as poly I:C and ISCOMs, that modulate Ag processing and have potent innate activity, can enhance the magnitude, quality, and phenotype of T cell immunity.
authors.affiliation: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Kylie M
authors.initials: KM
authors.lastname: Quinn
authors.forename: Ayako
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Andreia
authors.initials: A
authors.lastname: Costa
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Darrah
authors.forename: Ross W B
authors.initials: RW
authors.lastname: Lindsay
authors.forename: Sonia T
authors.initials: ST
authors.lastname: Hegde
authors.forename: Teresa R
authors.initials: TR
authors.lastname: Johnson
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Flynn
authors.forename: Karin
authors.initials: K
authors.lastname: Loré
authors.forename: Robert A
authors.initials: RA
authors.lastname: Seder
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D016882:ISCOMs / Q000008:administration & dosage / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000008:administration & dosage / Q000276:immunology*; D020825:T-Box Domain Proteins / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014615:Vaccinia / Q000276:immunology / Q000517:prevention & control; D014616:Vaccinia virus / Q000276:immunology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D016882:ISCOMs; D007376:Interleukin-2; D053699:Interleukin-7 Receptor alpha Subunit; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D054301:gag Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma; D011070:Poly I-C